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Human mutations in neuropeptide Y (NPY) have been linked to high body mass index but not altered dietary patterns1. Here we uncover the mechanism by which NPY in sympathetic neurons2,3 protects from obesity. Imaging of cleared mouse brown and white adipose tissue (BAT and WAT, respectively) established that NPY+ sympathetic axons are a smaller subset that mostly maps to the perivasculature; analysis of single-cell RNA sequencing datasets identified mural cells as the main NPY-responsive cells in adipose tissues. We show that NPY sustains the proliferation of mural cells, which are a source of thermogenic adipocytes in both BAT and WAT4–6. We found that diet-induced obesity leads to neuropathy of NPY+ axons and concomitant depletion of mural cells. This defect was replicated in mice with NPY abrogated from sympathetic neurons. The loss of NPY in sympathetic neurons whitened interscapular BAT, reducing its thermogenic ability and decreasing energy expenditure before the onset of obesity. It also caused adult-onset obesity of mice fed on a regular chow diet and rendered them more susceptible to diet-induced obesity without increasing food consumption. Our results indicate that, relative to central NPY, peripheral NPY produced by sympathetic nerves has the opposite effect on body weight by sustaining energy expenditure independently of food intake.We find that, relative to central neuropeptide Y, peripheral neuropeptide Y produced by sympathetic nerves has the opposite effect on body weight by sustaining energy expenditure independently of food intake. [ABSTRACT FROM AUTHOR]

Hypothalamic pro-opiomelanocortin (POMC) neurons promote satiety. Cannabinoid receptor 1 (C[B.sub.1]R) is critical for the central regulation of food intake. Here we test whether C[B.sub.1]R-controlled feeding in sated mice is paralleled by decreased activity of POMC neurons. We show that chemical promotion of C[B.sub.1]R activity increases feeding, and notably, C[B.sub.1]R activation also promotes neuronal activity of POMC cells. This paradoxical increase in POMC activity was crucial for C[B.sub.1]R -induced feeding, because designer-receptors-exclusively-activated-by-designer-drugs (DREADD)-mediated inhibition of POMC neurons diminishes, whereas DREADD-mediated activation of POMC neurons enhances C[B.sub.1]R-driven feeding. The Pomc gene encodes both the anorexigenic peptide a-melanocyte-stimulating hormone, and the opioid peptide β-endorphin. C[B.sub.1]R activation selectively increases β-endorphin but not α- melanocyte-stimulating hormone release in the hypothalamus, and systemic or hypothalamic administration of the opioid receptor antagonist naloxone blocks acute C[B.sub.1]R -induced feeding. These processes involve mitochondrial adaptations that, when blocked, abolish C[B.sub.1]R -induced cellular responses and feeding. Together, these results uncover a previously unsuspected role of POMC neurons in the promotion of feeding by cannabinoids., Feeding behaviour is under the control of hypothalamic circuits (1). In the hypothalamic arcuate nucleus (ARC), Agouti-related peptide (AgRP)expressing neurons, when activated, promote food intake (2,3), whereas POMC-producing neurons promote [...]

There are no clinically relevant treatments available that improve function in the growing population of very preterm infants (less than 32 weeks' gestation) with neonatal brain injury. Diffuse white matter injury (DWMI) is a common finding in these children and results in chronic neurodevelopmental impairments (1,2). As shown recently, failure in oligodendrocyte progenitor cell maturation contributes to DWMI3. We demonstrated previously that the epidermal growth factor receptor (EGFR) has an important role in oligodendrocyte development (4). Here we examine whether enhanced EGFR signalling stimulates the endogenous response of EGFR-expressing progenitor cells during a critical period after brain injury, and promotes cellular and behavioural recovery in the developing brain. Using an established mouse model of very preterm brain injury, we demonstrate that selective overexpression of human EGFR in oligodendrocyte lineage cells or the administration of intranasal heparinbinding EGF immediately after injury decreases oligodendroglia death, enhances generation of new oligodendrocytes from progenitor cells and promotes functional recovery. Furthermore, these interventions diminish ultrastructural abnormalities and alleviate behavioural deficits on white-matter-specific paradigms. Inhibition of EGFR signalling with a molecularly targeted agent used for cancer therapy demonstrates that EGFR activation is an important contributor to oligodendrocyte regeneration and functional recovery after DWMI. Thus, our study provides direct evidence that targeting EGFR in oligodendrocyte progenitor cells at a specific time after injury is clinically feasible and potentially applicable to the treatment of premature children with white matter injury., Chronic neonatal hypoxia is a clinically relevant model of premature brain injury caused by insufficient gas exchange from poor lung development (5). This 'hypoxic' state is a major contributor to [...]

The gut-derived hormone ghrelin exerts its effect on the brain by regulating neuronal activity. Ghrelin-induced feeding behaviour is controlled by arcuate nucleus neurons that co-express neuropeptide Y and agouti-related protein [...]

Author(s): Michael A. Cowley [1, 2]; James L. Smart [1, 2]; Marcelo Rubinstein [3]; Marcelo G. Cerdán [3]; Sabrina Diano [4]; Tamas L. Horvath [4, 5]; Roger D. Cone (corresponding [...]

Nature 454, 846-851 (2008) In Fig. 3a and b of this Article, the pAMPK samples were spliced. Images of the uninterrupted AMPK together with the uninterrupted pAMPK samples are now [...]

A correction to the article "UCP2 Mediates ghrelin's action on NPY/AgRP Neurons by lowering free radicals," that was published in 2008 issue is presented.